. PROJECT SUMMARY (See instructions): During our life time, homeostatic signaling systems secure the integrity of neuronal circuits while allowing some flexibility that will be the basis for processes of cognition, learning and memory. It is therefore not surprising that a series of neurobiological diseases (autism spectrum disorder, Alzheimer's disease and schizophrenia, among them) have been linked to alterations in homeostatic mechanisms. Despite the tremendous importance of understanding neuronal homeostasis and how homeostatic signaling systems interact with neuronal plasticity, we know close to nothing about the molecular mechanisms underlying synaptic homeostasis. We have recently discovered that the highly conserved BK-type K+ channel, slowpoke (slo) is essential to the homeostatic control of synaptic function. This study will define a new function for slo while characterizing a new molecular mechanism for the homeostatic stabilization of neuronal function. In human, mutation in slo has been implicated in generalized epilepsy and paroxysmal dyskinesia, slo is also known to control the active properties of neurons and skeletal muscles, to be essential to aspects of synaptic plasticity and alcohol addiction, and to bind to really important signaling molecules, including Ca2+ channels. This study will combine quintal analysis of different mutant backgrounds, pharmacology, molecular genetics, biochemistry and activity dependent Ca2+ imaging using two-photon microscopy to show that (1)- the modification of Ca2+ influx is the mechanism at the heart of homeostatic plasticity and that this mechanism depends on presynaptic slo. (2)- Slo conductance is not required to perform this function; the Slo C-terminus tail is sufficient to restore homeostasis, illustrating a new essential function for the regulatory Slo sequences. (3)- the Slo C-terminus tail interacts with the Ca2+ channel responsible for neurotransmitter release, CaV2.1 (Cae). This interaction is required for the upregulation of Cae during synaptic homeostasis.